Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies

Autor: Ashenafi Y. Tilahun, Andrew Leishman, Richard J. A. Goodwin, John P. Vasilakos, Robert W. Wilkinson, John G. Swales, Nadia Luheshi, Elina Timosenko, Ronald Herbst, James Elvecrog, Stefanie R. Mullins, Simon J. Dovedi, Pete Gillis, Zachary A. Cooper, Iwen Grigsby, Katharina Deschler, Julius John, Matthew J. Elder, Mark A. Tomai
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Cancer Research
medicine.medical_treatment
Melanoma
Experimental
Apoptosis
Adaptive Immunity
Rats
Sprague-Dawley
Mice
0302 clinical medicine
Tumor Cells
Cultured
Tumor Microenvironment
Immunology and Allergy
Mice
Inbred BALB C
Chemistry
virus diseases
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Acquired immune system
Killer Cells
Natural
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
Female
Immunotherapy
Heterocyclic Compounds
3-Ring
Stearic Acids
Research Article
Agonist
medicine.drug_class
Ovalbumin
T cell
Immunology
T cell agonist
lcsh:RC254-282
03 medical and health sciences
Immune system
Adjuvants
Immunologic
TLR
medicine
Animals
Humans
Cell Proliferation
Pharmacology
Tumor microenvironment
Innate immune system
Dendritic Cells
Immune checkpoint
Mice
Inbred C57BL
030104 developmental biology
Toll-Like Receptor 7
Toll-Like Receptor 8
Cancer research
Immune checkpoint blockade
Zdroj: Journal for Immunotherapy of Cancer
Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-18 (2019)
ISSN: 2051-1426
Popis: Background Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically “cold” tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated. Methods The response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models. Results Targeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNα, IL-12 and IFNγ. In contrast, a STING or a TLR9 agonist primarily induces release of IFNα. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8+ T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models. Conclusion Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists. Electronic supplementary material The online version of this article (10.1186/s40425-019-0724-8) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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